《生命科学》 2026, 38(6): 1028-1041
衰老与阿尔茨海默病的系统性关联：从共性机制到多靶点干预
摘 要：
随着人口老龄化加速，阿尔茨海默病（Alzheimer’s disease，AD）的疾病负担日益加重。目前靶向Aβ的疗法带来的认知改善有限，提示AD防治亟需探索突破单一靶点的新策略。衰老是AD最核心的风险因素，也是患者认知功能下降的重要促进因素，其通过从分子、细胞到系统层面的渐进性功能衰退，构成AD发生发展的生物学基础。基于衰老与AD在多层次上的复杂性、系统性关联，我们提出未来防治应演进为“病理事件干预-系统性年轻化-神经保护和脑网络重塑”的协同整合模式。这一多靶点、动态调整的策略，为突破当前治疗瓶颈、实现AD有效防控与促进健康老龄化提供了理论依据与新的研究方向。
通讯作者：王延江 , Email:yanjiang_wang@tmmu.edu.cn
Abstract:
With the accelerating trend of population aging, the burden of Alzheimer′s disease (AD) continues to rise. Current disease-modifying therapies that target β-amyloid (Aβ) have demonstrated clear biological efficacy in clearing cerebral Aβ plaques; however, their ability to delay overall cognitive decline remains limited, and the clinical benefits have not yet reached the anticipated threshold. This discrepancy underscores the urgent need to develop systemic prevention and treatment paradigms that transcend single-target approaches and enable multi-level intervention. Aging, the predominant risk factor for AD, drives disease initiation and progression through multi-layered mechanisms, including disruption of molecular homeostasis, cellular functional decline, and systemic regulatory dysregulation. Collectively, these age-dependent changes establish a permissive microenvironment that substantially lowers the threshold for neurodegeneration. Within the brain, aging drives a cascade of interrelated pathological processes, including elevated oxidative stress, aberrant activation of microglia and astrocytes, and sustained neuroinflammation. Critically, it also directly promotes abnormal aggregation of pathogenic proteins. The brain is not an anatomically isolated organ; rather, its structural integrity, functional homeostasis, and adaptive plasticity are dynamically regulated by systemic signaling networks emanating from peripheral organs. Peripheral aging further accelerates brain aging through the “body–brain axis” interaction network: age-related deterioration of the cardiovascular system and skeletal muscle directly elevates the biological age of the brain. Furthermore, peripheral aging disrupts central Aβ metabolic homeostasis—not only by increasing Aβ production (driven in part by platelet hyperactivation and gut dysbiosis) but also by impairing Aβ clearance mechanisms, particularly those mediated by the liver and kidney. In addition, systemic comorbidities such as obesity and hypertension further aggravate AD-related neuropathology and heighten disease susceptibility. Given the complex and multi-layered interplay between aging and AD, this review advocates for a paradigm shift in future preventive and therapeutic strategies toward an integrative and coordinated framework. This framework comprises three core pillars: intervention on pathological events (clearing pathological proteins and blocking associated cascades), systemic rejuvenation (ameliorating comorbid factors and decelerating the aging background), and neuroprotection and brain network remodeling (enhancing neuronal resilience and rebuilding brain networks). This multi-pronged strategy simultaneously addresses the upstream aging drivers and the downstream pathological consequences. Such a multimodal, dynamically adjustable approach not only provides a solid theoretical foundation and a translational pathway for overcoming existing therapeutic bottlenecks, but also establishes a scientific basis and practical direction for achieving comprehensive life-course prevention and control, precision management of AD, and supporting national strategic goals for healthy aging.
Communication Author：WANG Yan-Jiang , Email:yanjiang_wang@tmmu.edu.cn
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